Scattered across our genome are endogenous retroviruses (ERVs), ancient “footprints” of previous viral infections. Scientists do not fully understand their functions, but Zeng et al. now report a role for ERVs in mobilizing a particular type of B cell–driven immune response in mice [T cell–independent (TID)], which is usually mounted in response to viral capsids or bacterial polysaccharides (see the Perspective by Grasset and Cerutti). Immunizing mice with a model TID antigen elicited an increase in ERV RNA and DNA in the cytoplasm of B cells. Innate immune receptors that recognize cytoplasmic nucleotides then triggered signaling cascades that resulted in the production of immunoglobulin M.